Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, 1081 HV Amsterdam, Netherlands.
Science. 2010 Oct 15;330(6002):336. doi: 10.1126/science.1192632. Epub 2010 Sep 16.
Heterozygous somatic mutations in the genes encoding isocitrate dehydrogenase-1 and -2 (IDH1 and IDH2) were recently discovered in human neoplastic disorders. These mutations disable the enzymes' normal ability to convert isocitrate to 2-ketoglutarate (2-KG) and confer on the enzymes a new function: the ability to convert 2-KG to d-2-hydroxyglutarate (D-2-HG). We have detected heterozygous germline mutations in IDH2 that alter enzyme residue Arg(140) in 15 unrelated patients with d-2-hydroxyglutaric aciduria (D-2-HGA), a rare neurometabolic disorder characterized by supraphysiological levels of D-2-HG. These findings provide additional impetus for investigating the role of D-2-HG in the pathophysiology of metabolic disease and cancer.
异柠檬酸脱氢酶-1 和 -2（IDH1 和 IDH2）基因的杂合体细胞突变最近在人类肿瘤疾病中被发现。这些突变使酶失去将异柠檬酸转化为 2-酮戊二酸（2-KG）的正常能力，并赋予酶新的功能：将 2-KG 转化为 D-2-羟基戊二酸（D-2-HG）的能力。我们在 15 名患有 D-2-羟戊二酸尿症（D-2-HGA）的无关联患者中检测到 IDH2 的异合性子代突变，该疾病是一种罕见的神经代谢疾病，其特点是 D-2-HG 的生理水平升高。这些发现为研究 D-2-HG 在代谢性疾病和癌症的病理生理学中的作用提供了更多动力。
